Pharmaceutical compositions for the treatment of inner ear disorders

ABSTRACT

The present invention provides compositions containing (i) a pharmaceutically active agent selected from a group consisting of an arylcycloalkyamine or a derivative, analogue or pharmaceutically active salt thereof, and (ii) a biocompatible polymer or a combination of biocompatible polymers. These compositions or medicaments containing these compositions may be used for the prevention and/or treatment of inner ear diseases, e.g. tinnitus.

FIELD OF THE INVENTION

The present invention relates to compositions of one or morepharmaceutical compounds for the prevention and/or treatment of tinnitusand other disorders of the inner ear.

BACKGROUND OF THE INVENTION

Various inner ear disorders, e.g. hearing loss, inner ear infectiousdisease or tinnitus, have attracted increased interest with the objectto provide new therapies. E.g. tinnitus, the perception of sound withoutexternal acoustic stimulation, is a very common inner ear disorder. Anestimated 7% to 14% of the population have talked with their physicianabout tinnitus, while potentially disabling tinnitus occurs inapproximately 1% to 2.4% of people (Vesterarger V., British MedicalJournal 314 (7082): 728-731 (1997)). Tinnitus is often associated withother hearing disorders, such as hearing loss or hyperacusis, i.e.hypersensitivity to sound (Sahley T. and Nodar R., Hearing Research(152): 43-54), and quite often originates in the inner ear.

Various pharmaceutical compounds have already been tested in animalmodels or in human beings for the treatment of inner ear diseases, e.g.tinnitus, such as lidocaine, gabepentin, nortryptline, melatonin,caroverine, baclofen, alprazolam, gacyclidine, 7-chlorokynurenate, orketamine. While some of them have shown great promise, none of them isin regular clinical use, yet. One of the key obstacles to thedevelopment of effective treatments has been the fact that the inner earis protected like the brain by a biological barrier. For systemic drugadministration, relatively high doses are usually required to achieve adesired therapeutic effect in the inner ear, carrying the risk of potentside effects on the central or peripheral nervous system. Topicaladministration to the inner ear on the other side allows for a targeteddelivery of compounds with much lower doses required, as shown by innerear pharmacokinetic studies (Chen et al., Audio. Neurootol. 8: 49-56(2003)). Access to the inner ear may be achieved through a variety ofmiddle-inner ear interface tissue structures, such as the round windowmembrane, the oval window/stapes footplate, the annual ligament or theendolymphatic sac/endolymphatic duct.

Topical administration of the compound to the inner ear may beaccomplished by various delivery techniques. These include the use ofdevices to transport and/or deliver the compound in a targeted fashionto the membranes of the round or oval window, where it diffuses into theinner ear or is actively infused. Examples are otowicks (see e.g. U.S.Pat. No. 6,120,484 to Silverstein), round window catheters (see e.g.U.S. Pat. Nos. 5,421,818; 5,474,529; 5,476,446; 6,045,528; all toArenberg, or U.S. Pat. No. 6,377,849 and its division 2002/0082554 toLenarz), or microimplants (see e.g. WO2004/064912 by Jukarainen et al.).They further include the use of devices which are inserted into thecochlear duct or any other part of the cochlea (see e.g. U.S. Pat. No.6,309,410 to Kuzma). Another delivery technique is transtympanicinjection (sometimes also called “intratympanic injection”), whereas themedication is injected through the tympanic membrane into the middle eartypically for diffusion across the round window membrane (for adescription see e.g. Light J. and Silverstein H., Current Opinion inOtolaryngology & Head and Neck Surgery (12): 378-383 (2004). It has beenused in clinical practice for a long time and is a relatively minorintervention, which can be carried out in a doctor's office. Forrepeated injections, a middle ear ventilation tube may be inserted intothe tympanic membrane, through which the medication can be administeredinto the middle ear space. Drug carriers that are too viscous to beinjected may also be deposited across a small opening in the tympanicmembrane with the aid of surgical instrument.

In order to increase the therapeutic efficacy of pharmaceuticalcompounds for inner ear therapy, particular formulations with gels,foams or fibrins or other drug carriers can be used. They may providefor the controlled release of the drug over an extended period of timesuch as hours, days or weeks, improve its diffusion into the inner earby increasing the permeability of the middle-inner ear interface tissuestructure or by keeping the formulation in continuous contact with suchstructure. This compares favourably to the administration of thepharmaceutical compound in a solution, where multiple injections mightbe required, drug percolation back into the ear canal or significantloss down the Eustachian tube could result, and continuous contact withthe middle-inner ear interface tissue structure might be difficult orimpossible to achieve. Ideally, the drug carrier is biocompatible aswell as biodegradable, in which case there is no need for subsequentremoval.

The diffusion of pharmaceutical compounds across middle-inner earinterface tissue structures, in particular the round window membrane,depends on a variety of factors, such as molecular weight,concentration, liposolubility, electrical charge, and thickness of themembrane (Goycoolea M. and Lundman L., Microscopy Research and Technique36: 201-211 (1997)). In the absence of experimental data obtained invivo or with membrane tissue, the capacity to cross middle-inner earinterface tissue structures and thus the suitability of anypharmaceutical compound or formulation for topical administration to theinner ear remains unknown.

Selivanova et al., Laryngo-Rhino-Otol (82): 235-239 (2003) demonstratein vivo that hyaluronic acid increases the permeability of the roundwindow membrane and that the test substance lidocaine is thus morerapidly diffused into the inner ear and produces a larger effect.Chandrasekhar S., Otology & Neurotology (22): 18-23 (2001) show in vivothat transtympanic injection of dexamethasone with histamine results inhigher concentrations of this steroid in the perilymph of the inner earthan if administered without.

There exists vast literature concerning (topical) administration ofpharmaceutical compounds to treat inner ear diseases. Steroids andaminoglycosides have been administered locally to the inner ear inclinical practice for quite some time (see e.g. Hoffer et al.,Otolaryngologic Clinics of North America (37): 1053-1060 (2004)). Sakataet al., International Tinnitus Journal (2): 129-135 (1996), describe theintratympanic infusion of dexamethasone into the tympanic cavity ofhuman beings. Hoffer et al., Otolaryngologic Clinics of North America(36): 353-358 (2003), describe transtympanic injections ofmethylprednisolone solutions for the treatment of tinnitus followingnoise trauma or sudden deafness. In all these cases, the drug compoundswere applied in solutions. However, there is less known about topicaltreatment of inner ear diseases with other formulations.

WO1997/38698 by Manning et al. teaches the use of biocompatible polymersto deliver pharmaceutical compounds to the inner ear for treating middleand inner ear diseases, e.g. Meniere's disease or viral and bacterialinfection diseases. Experimental in vitro release data is shown for ahyaluronic acid formulation with gentamicin.

WO2004/022069 by Puel et al. describes the delivery of neuromodulatoryagents, in particular the NMDA antagonists gacyclidine, D-AP5, MK 801and 7-chlorokynurenate, with a variety of formulations, including drugcarriers such as gelfoam, hyaluronic acid, or fibrin glue for thetreatment of various inner ear diseases. Moreover, a plurality ofalternative insertion methods for administration of the formulation intothe middle ear is described by WO2004/022069.

In the light of the literature above and the disadvantages involved withmany of the pharmaceutical compositions used so far for topicaladministration there is a need for other pharmaceutical compositionsappropriate for topical treatment of inner ear disorders, which can beeasily injected into the middle ear, release the drug over an extendedperiod of time, and allow for a high percentage of the drug to bedelivered into the inner ear.

SUMMARY OF THE INVENTION

The present invention provides compositions containing (i) apharmaceutically active agent selected from a group consisting of anarylcycloalkyamine or a derivative, analogue or pharmaceutically activesalt thereof, and (ii) a biocompatible polymer or a combination ofbiocompatible polymers. These compositions or medicaments containingthese compositions may be used for the prevention and/or treatment ofinner ear diseases, e.g. tinnitus.

The composition of the present invention comprises a biocompatiblepolymer support incorporating a therapeutically effective amount of at(east one pharmacologically active agent as defined above. Thearylcycloalkylamine agent may e.g. suppress or reduce the perception oftinnitus. Preferably, the composition is formulated such that, upondelivery into the middle ear, it is capable of remaining in contact withat least one of the middle-inner ear interface tissue structures andproviding extended release of the pharmacologically active agent intothe inner ear. Preferably, the biocompatible polymer is biodegradable aswell and may also increase the permeability of the target middle-innerear interface tissue structure to enhance diffusion of thepharmacologically active agent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the cumulative release of S-(+)-Ketamine from 5% and 7.5%hyaluronic acid gel formulations into phosphate buffer solution overtime.

FIG. 2 shows the concentration of S-(+)-Ketamine in perilymph afterbeing released from a 2.8% hyaluronic acid formulation that had beenplaced into the round window niche of guinea pigs and then diffusedacross the round window into the inner ear.

FIG. 3 shows the concentration of S-(+)-Ketamine in perilymph afterbeing released either from a 0.7% hyaluronic acid formulation or a 20%poloxamer formulation that had been injected into the round window nicheof guinea pigs and then diffused across the round window into the innerear.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on experimental findings withcompositions, which are in particular suitable for topicaladministration of an arylcycloalkylamine, or a derivative, analogue orpharmaceutically active salt thereof, particularly for the treatment ofinner ear disorders.

The inventive formulation contains as main pharmacologically activeagent a compound of the class of arylcycloalkylamines. Among the classof arylcycloalkylamines compounds having the general formula I

wherein R1, R2, R3, R4, R5, R6 and R7 are H, Cl, F, I, CH₃, CH₂CH₃, NH₂,OH, CONH₂, COCl or COOH are preferred.

One of the particularly preferred compounds of the class ofarylcycloalkylamines is ketamine. Ketamine (C₁₃H₁₆ClNO (free base),2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone), the structuralformula of which is

is a non-competitive NMDA-receptor antagonist which binds to thePCP-binding site, a separate site of the NMDA-receptor complex locatedwithin the ion channel, thereby blocking the transmembranous ion flux.

Any derivative, analogue, and/or enantiomeric form of ketamine or anarylcycloalkylamine compound as defined by formulae II or I,respectively, may be used as active agent in the inventive composition.

Ketamine may be provided by methods disclosed in U.S. Pat. No.3,254,124. More specifically, the preferred compound is (S)-Ketamine, asit binds with a 3-4-fold higher affinity to the PCP binding site of theNMDA receptor than (R)-ketamine (Vollenweider et al., Eur.Neuropsychopharmacol. 7: 25-38 (1997)). The synthesis of the opticalisomers may be carried out as described by DE 2062620 or WO01/98265,which are incorporated herein by reference.

The arylcycloalkylamine compound contained within the pharmaceuticalcomposition of this invention may be provided in the form of apharmaceutically acceptable salt. Examples of such a salt include, butare not limited to, those formed with organic acids (e.g. acetic,lactic, citric, malic, formaric, tartaric, stearic, ascorbic, succinic,benzoic, methanesulfonic, toluenesulfonic, or pamoic acid), inorganicacids (e.g., hydrochloridic, nitric, diphosphoric, sulphuric, orphosphoric acid), and polymeric acids (e.g., tannic acid, carboxymethylcellulose, polylactic, polyglycolic, or co-polymers ofpolylactic-glycolic acids). In a preferred embodiment of the presentinvention ketamine may be administered as hydrochloride salt(C₁₃H₁₇Cl₂NO) of its free base form.

The invention relates to compositions that incorporate anarylcycloalkylamine agent, eventually in combination with at least oneother pharmacologically active agent. It may be formulated such that itcan be topically administered into the middle ear for controlled releaseof the agent with the objective of maximizing its passage into the innerear. Preferably, the composition is adhered to the selected middle-innerear interface tissue structure by bio-adhesion or mechanical properties.

The biocompatible polymer contained in the inventive composition maysupport this objectives primarily through two mechanisms. First, byensuring that the pharmaceutical compound is delivered to the targetmiddle-inner ear interface tissue structure from where it is to diffuseinto the inner ear. For this purpose the polymer must remain at thetarget site for the time that is necessary to achieve the desiredduration and effect of the pharmacological treatment either by adhesionto the local middle ear mucosa or through viscous properties, whichensure that the formulation remains in place. Second, by increasing thepermeability of the target middle-inner ear interface tissue structurein order to facilitate passage of the pharmaceutical compound into theinner ear.

The composition containing the pharmaceutically activearylcycloalkylamine agent (in the following description often simplydesignated as “active agent”) can have a solid, semi-solid, gel-like, orliquid state. Preferably, the composition is a solution, suspension, anemulsion or a thermosetting gel.

The inventive composition contains a biocompatible polymer or acombination of biocompatible polymers. The biocompatible polymer(s) aredefined in that they are substantially non-reactive with respect to thehuman/animal body or bodily fluid. They can be natural, such asnaturally occurring polysaccharides, or synthetic in origin.

Preferably, the polymer contained in the composition is degraded invivo, either hydrolytically or enzymatically, to produce biocompatible,toxicologically safe by-products that are further eliminated by thenormal metabolic pathways. A variety of natural, synthetic andbiosynthetic polymers are biodegradable. A polymer based on a C—Cbackbone tends to be nonbiodegradable, whereas heteroatom-containingpolymer backbones confer biodegradability. Biodegradability cantherefore be engineered into polymers by the appropriate addition ofchemical linkages such as anhydride, ester or amide bonds, among others.The degradation is effected by hydrolysis or enzymatic cleavageresulting in a scission of the polymer backbone. Preferred arebiodegradable polymers with hydrolysable chemical bonds.

In order to be used in medical compositions the biodegradable polymermust be biocompatible and preferably meet other criteria, such as beingbiomaterial-processable, sterilizable and capable of controlledstability or degradation in response to biological conditions.Therefore, the degradation products often define the biocompatibility ofa polymer, not necessarily the polymer itself.

Poly(esters) based on polylactide (PLA), polyglycolide (PGA),polycaprolactone (PCL) and their copolymers are useful polymers inpharmaceutical compositions. Degradation of these materials yields thecorresponding hydoxy acids, making them safe for in vivo use. Otherbiodegradable polymers include e.g. polyhydroxyalkanoates of the PHB-PHVclass, additional polyesters and natural polymers, particularly,modified polysaccharides, e. g. starch, cellulose and chitosan.

The biocompatible polymer can also be selected from block (co)polymers.E.g. multiblock copolymers of poly(ethylene oxide), PEO, andpoly(butylene terephthalate), PBT, may be suitable materials. Thesematerials are subject to both hydrolysis (via ester bonds) and oxidation(via ether bonds). Degradation rate is influenced by PEO molecularweight and content. The copolymer with the highest water uptake degradesmost rapidly.

The inventive compositions may contain a homogeneous form of abiocompatible polymer or may contain mixtures of one, two or moredifferent polymers, which may be prepared due to a variety of polymersobtained by the production methods resulting in inhomogeneous polymerproduction or by combining different polymers in a separate mixing step.

The biocompatible polymer used in the present composition preferably canform gels, which may be biodegradable or non-biodegradable, aqueous ornon-aqueous, or microsphere based.

Examples of gel forming biocompatible polymers include, but are notlimited to, hyaluronic acid resp. hyaluronates, lecithin gels,(poly)alanine derivatives, pluronics, poly(ethyleneglycol), poloxamers,chitosans, xyloglucans, collagens, fibrins, polyesters, poly(lactides),poly(glycolide) or their co-polymers PLGA, sucrose acetate isobutyrate,and glycerol monooleate. Preferred are gels which can be easilyadministered into the middle ear, release the drug over an extendedperiod of time, and allow for a high percentage of the drug to bedelivered into the inner ear.

Hyaluronic acid, which is preferably used as biocompatible polymer inthe inventive composition, is a physiological substance that is widelydistributed in the extracellular matrix of connective tissues in allorgans of the body. It occurs in various molecular weights and isreported to be non-antigenic. Moreover, it has an excellentbiocompatibility and is also biodegradable. These high molecular weightpolymers are widely used in the pharmaceutical and cosmetic industries,e.g. as an ophthalmosurgical aid in various anterior procedures, such asintra- and extra capsular cataract surgery, intraocular lensimplantation, keratoplasty, glaucoma surgery and post-trauma surgery.Hyaluronic acids have also found applications in treatment of jointproblems. Hyaluronic acid is a naturally occurring polysaccharide, aglycosaminoglycan composed of a long-chain polymer containing repeatingdisaccharide units of Na-glycuronate-N-acetylglucosamine. The mainproperties of hyaluronic acid are that it binds water and hence forms adegradable gel with high viscosity. The viscosity of the hyaluronic acidsolutions increases with concentration and molecular weight.Pharmaceutically active agents can be either dissolved or suspended inthe hyaluronic acid gel.

Phospholipids in conjunction with some other additives have been shownto provide a very promising topical drug delivery vehicle, i.e.,lecithin organogel (LO). LOs are thermodynamically stable, clear,viscoelastic, biocompatible, and isotropic gels composed ofphospholipids (lecithin), appropriate organic solvent and a polarsolvent. The jelly-like phases consist of a three-dimensional network ofentangled reverse cylindrical (polymerlike) micelles, which immobilizesthe continuous or macroscopic external organic phase, thus turning aliquid into a gel. The formation of a three-dimensional network in theorganogel is the result of transition at the micellar level in a lowviscous newtonian liquid consisting of lecithin reverse micelles innonpolar organic liquid. This spherical reverse micellar state of lipidaggregates, turns on to form elongated tubular micelles with theaddition of water, and subsequently entangle to form a temporalthree-dimensional network in the solution bulk. The latter serves toimmobilize the external organic phase, thus producing a gel form or thejelly-like state of the initial nonviscous solution.

Poly(ethyleneglycol), PEG, is a derivative of Poly(ethylene oxide), PEO,which has in addition hydroxyl groups at each end of the molecule. Keyproperties that make PEG attractive as polymer in pharmaceuticalcompositions are biocompatibility, hydrophilicity and versality. Thesimple, water-soluble linear polymer can be modified by chemicalinteraction to form water-insoluble but water-swellable hydrogels.Absorbent polymers which may function as hydrogels can be prepared e.g.by subjecting the polymers to covalent cross-linking or creatingassociative polymers consisting of hydrophilic and hydrophobiccomponents (“effective” cross-links through hydrogen bonding).

Thermosetting gels comprise polymers that are fluid at low temperature,but form highly viscous, near solid implants upon placement at a site atbody temperature. The most common of these reversible thermosettingsystems are poloxamers. When dissolved at concentrations above 20%(w/w), the solutions will remain fluid at low temperatures, but willform highly viscous, solid-like implants upon an increase in temperature(usually around 15° C.). The exact gelation temperature can be alteredby changing the poloxamer content or by the addition of otherexcipients. Once in place, soluble drugs are released by diffusionthrough the polymer. The polymeric implants do not remain intact forlong. At sites where fluid flow is significant (e.g., subcutaneousspace), the implants may remain for a period of up to 12-24 hours. Thepoloxamers are not biodegradable, as they are polyethers (blockco-polymers of polyoxyethylene and polyoxypropylene). They are excretedintact in the urine, as they are relatively low molecular weightpolymers (<20 kD). They can carry a sizeable drug load, although thereis a significant burst effect, especially for hydrophilic drugs. Thekinetic profile for hydrophobic drugs tends to be retarded, presumablyby sequestration of the drug within a hydrophobic core of the implant.

Thermosetting gels that are biodegradable and have slower releasecharacteristics than poloxamers include PLA-PEG or triblock copolymersof PEG-PLGA-PEG. As with the poloxamer systems, they are fluid at lowtemperature. Upon administration they form a semi-solid gel.

Chitin is the second most abundant natural polymer in the world aftercellulose. Upon deacetylation, it yields the biomaterial Chitosan, whichupon further hydrolysis yields an extremely low molecular weightoligosaccharide. Chitosan has biocompatible and antibacterialproperties. A chitosan-glyceroiphosphate solution is able to form areversible thermosetting gel. Again, it is fluid at low temperatures andforms a semi-solid upon administration at body temperature. For example,this system can be used to deliver growth hormone. Chitosan remainssoluble in water up to pH 6.2. Any pH above this value leads to chargeneutralization and precipitation of the polymer. Addition of sugar-basedphosphates transformes chitosan into a thermo-reversible gel drugdelivery system.

Besides the thermally reversible gels other stimuli-responsive polymerswhich are critically reliant on the balance between polymer-polymer andpolymer-solvent interactions under various stimuli including changes intemperature, pH, ionic strength, solvent concentration, pressure, sheerstress, light intensity, electric or magnetic fields or a combination ofthese factors may be suitable in the present composition. An example ofa pH-reversible hydrogel is the aqueous solution of poly(acrylic acid)polymer, which undergoes a pH-mediated phase transition atconcentrations above 0.1% by weight.

The stimulus-sensitive gel may be also formed from an enzymaticallydegradable polypeptide polymer. The polypeptide bonds in the polypeptidepolymer are more stable against hydrolysis than e.g. the ester bonds inPEG/PLGA polymer systems, thereby also providing superior storagestability. The polypeptide carrier may also include a biodegradablepolymer having a biodegradable polypeptide block linked to a secondpolymer block to form a graft or linear polymer. An example for apolypeptide polymer is poly(alanine) and derivatives thereof. Thepolypeptide carrier may also be a protein matrix known as fibrin.Fibrinogen is a naturally occurring protein which, when combined withthe enzyme thrombin, another naturally occurring protein, forms abio-matrix known as fibrin

Other biocompatible polymers may also be used including starch,celluloses, gelatins pluronics, tetronics, the latter two being poly(ethylene oxide)/poly (propylene oxide) materials. Other materials thatmay be used include the chondroitin sulfates and the general class ofmucopolysaccharides (e.g., glycosaminoglycans) and other biocompatiblepolymers having characteristics similar to hyaluronic acid.

A medicament containing the inventive composition is preferably formedas a release-of-drug-formulation which releases the pharmaceuticallyactive agent(s) over several hours up to several weeks.

In a first embodiment of the present invention, the active agent(s)form(s) a core surrounded by an inert diffusion barrier formed by thebiocompatible polymer. These systems include e.g. membranes, capsules,microcapsules, liposomes and hollow fibers. Here, the release of theactive agent is mainly controlled by diffusion.

In a second embodiment, the composition comprises a solution of thebiocompatible polymer wherein the active agent is dissolved, emulsifiedor dispersed. As in reservoir systems, the diffusion of the activeagent(s) through the polymer matrix is the rate-limiting step, andrelease rates are determined by the choice of polymer and its consequenteffect on the diffusion and partition coefficient of the active agent tobe released.

In another embodiment of the present invention, the compositioncomprises a cross-linked polymer gel forming a macromolecular “cage” inwhich the active agent is dispersed. Alternatively, the presentcomposition may comprise a cross-linked mixed gel consisting of acombination of biocompatible hydrophilic polymers in which the activesubstance is dispersed.

In a further embodiment, the composition comprises a cross-linked gel ofthe biocompatible polymer or cross-linked mixed gel of at least twohydrophilic polymers containing the active agent which is covalentlyattached to the macromolecules of at least one of the polymers.

The release rate of pharmaceutical compounds from polymer based gels maybe extended by such cross-linking, whereas adjacent chains of thepolymer are joined by creating covalent bonds. The resultingcross-linked polymer breaks down more slowly and thus retains thepharmacologically active agent longer.

Various cross linking agents and methods for accomplishing cross linkingof biodegradable materials are well known in the art. Preferably, crosslinking is accomplished so that the final cross linked material for thedelivery unit are substantially non-toxic (e. g., by use of thermalcross linking, gamma irradiation, ultraviolet irradiation, chemicalcross linking, etc.). In general, the degree of cross linking relatesinversely to the degree of swelling or absorption of water by the shapedpolymer structure. The degree of swelling or water absorption regulatesthe rate of drug transport by the polymer structure.

In a further embodiment of the present invention the release of theactive agent from the polymer is chemically controlled. This control canbe achieved using bioerodible or pendant chains. Polymer bioerosion canbe defined as the conversion of a material that is insoluble in waterinto one that is water-soluble. In such a system the active agent isideally distributed uniformly throughout the polymer. As the polymersurrounding the active agent is eroded, the active agent escapes. In apendant chain system, the active agent is covalently bond to the polymerand is released by bond scission owing to water or enzymes. Insolvent-activated controlled systems, the active agent is dissolved ordispersed within a polymer matrix and is not able to diffuse through thematrix. In one type of solvent controlled systems, as the environmentalfluid, e.g. water, penetrates the matrix, the polymer swells and itsglass transition temperature is lowered below the environmentaltemperature. Thus, the swollen polymer is in a rubbery state and allowsthe drug contained within to diffuse through the encapsulant.

Another technique to extend the release rate of ionic compounds is byincorporating the pharmacologically active agent in a hydrophobic ionpair complex as described in WO1997/38698. Here, the pharmacologicallyactive agent may be present in the form of a hydrophobic ion paircomplex with an amphiphilic material. Preferred amphiphilic materialsfor forming a hydrophobic ion pair with the arylcycloalkylamine activeagent are sodium dodecyl sulfate (SDS) and bis-(2-ethylhexyl)sodiumsulfosuccinate (AOT). The hydrophobic ion pair complex may be preparedaccording to procedures known in the art. Additional informationconcerning hydrophobic ion pair complexes and their preparation may befound in PCT Publication No. WO 94/08599, published Apr. 28, 1994, andpending U.S. patent application Ser. No. 08/473,008, filed Jun. 6, 1995,the contents of both of which are incorporated herein in theirentireties.

It is also possible to combine the embodiments described above allowingthe controlled release of the active agent, for example by creating agel holding microspheres. There, the release of the active agent may becontrolled by the gel system as well as by the microspheres suspended inthe polymer gel system.

Most any of the viscous gel systems described above (e.g. hyaluronate)could be designed to hold suspended microspheres. The gel could providean intimate contact to the middle inner ear interface tissue structureand thus allow the transport of the active agent(s) through the membraneinto the inner ear by the microspheres. Active agent release ratesdepend very strongly on the size of the microspheres containing theactive agent, larger microspheres may generally release encapsulatedcompounds more slowly and over longer time periods. To achieve adelivery of the active agent at a constant rate it might be useful tomix microspheres of different sizes to generate a constant rate ofrelease over a prolonged period of time. Moreover, the gel containingthe microspheres may also contain substances increasing the permeabilityof the membrane so that the microspheres can pass the membrane moreeasily.

The different systems described above suitable for the controlledrelease of the active agent may also be included in an implant whichcould be placed e.g. at the round window membrane and delivers theactive agent in a controlled manner.

In one embodiment, the implant consists essentially of a carrier mediumwhich is combined with the active agent. The carrier medium may comprisethe biocompatible polymer which may be biodegradable or not, or acombination of biocompatible polymers which may be cross-linked. Thiscomposition may be formed such that it is injectable and modifies itsviscosity, e.g. from fluid to highly viscous or solid, upon insertioninto the middle ear, as described above for the thermosetting gels, e.g.poloxamers. Release of the active agent contained in the carrier mediummay be by diffusion, solvent drag, electrodiffusion, osmosis,active/passive transport or a combination thereof.

In another embodiment, the implant may comprise a core and at least onemembrane encasing the core. The core may comprise the compositionconsisting of the active agent(s) dissolved or dispersed in thebiocompatible polymer(s). The membrane can be made of the same or adifferent polymer composition than the core or an elastomer composition.In this implant the release rate of the active agent is controlled bythe properties of the core and optionally by the properties of themembrane(s). Thus, the release rate(s) of the active agents can becontrolled either by the core or membrane alone or by the membranetogether with the core. It is also possible, that the release rate ismainly controlled by the core and that the membrane performs only thefinal control of the release rate.

If the membrane encasing the core consists of two or more layers, thepolymer or elastomer compositions used in each layer may be same ordifferent. The combination of different layers of membrane either inthickness or in material or both gives a further possibility forcontrolling the release rate of the active agent(s).

If the implant comprises more than one pharmaceutically active agent,the core may consist of one part comprising the different active agentsdissolved or dispersed in the same polymer composition. In anotherembodiment, the core consists of at least two parts, each partcomprising at least one pharmaceutically active agent. The polymercompositions of the different parts of the core may be chosen accordingto the desired release rates of the different active agents and maytherefore same or different in each part. The different parts of thecore may be either positioned next to each other or in such a way thatone part of the core encases at least partly another part of the core.The different parts of the core may be either spaced from each otherand/or may be separated by a separating membrane. The separationmembranes may be permeable or impermeable to at least one of thepharmaceutically active agents. Also it is possible to use a membranewhich is permeable to a first active agent but impermeable to a secondactive agent.

Useful as materials of the membrane(s) of the implant are e.g.siloxan-based elastomers which are elastomers made of poly(disubstitudedsiloxanes) where the substituents mainly are lower substituted orunsubstituted alkyl or phenyl groups. A widely used and preferredpolymer of this kind is poly(dimethylsiloxane). Alsoethylene-vinylacetate copolymer membranes which can act as rate-limitingbarrier for the diffusion of the active agent may be suitable.

The release kinetics of the pharmacologically active agent are not onlygoverned by the release from the composition, but to a potentially evenmore important extent by the degree of permeation of the inner-middleear interface tissue structure.

Therefore, pharmaceutical compositions of this invention suited fortopical administration to the inner ear preferably contain substancesincreasing the permeability of the middle-inner ear interface tissuestructure in a way that the pharmacologically active agent can diffusein a given period of time in higher quantities or in a given quantitymore quickly into the inner ear or that a larger molecule could passinto the inner ear. Such improved permeation must come however withoutdisturbing the osmotic balance between inner ear perilymph and themiddle ear space and without inducing toxicity in the cochlea.Particular attention has to be paid to potential ototoxicity frompermeability enhancing substances, which may themselves pass across theround window and have a cytotoxic effect within the inner ear. It coulde.g. be shown that streptolysin does well increase round windowpermeability, yet at the price of cytotoxicity.

An example for a substance increasing the permeability of themiddle-inner ear interface tissue structure is histamine. Also,hyaluronic acid has been shown to increase the permeability of theinner-ear interface structure without ototoxicity and is thereforepreferably used as biocompatible polymer in the composition of thepresent invention.

The composition of the present invention may further comprise one ormore other pharmacologically active compounds. Otic compositions inaccordance with the present invention can comprise various ingredients,including other biologically-active-agents, such as antibiotics, e.g.,fluoroquinolones, anti-inflammatory agents, e.g., steroids, cortisone,analgesics, antipyrine, benzocaine, procaine, antioxidants, e.g.methionine, N-acetylcysteine, trolox, neurotrophins, e.g. GDNF or BDNF,anti-apoptotic or anti-necrotic agents, e.g. leupeptin, caspaseinhibitors, etc.

Pharmaceutical compositions of this invention suited for topicaladministration to the inner ear contain a therapeutically effectiveamount of active ingredient(s), and, as may be necessary, furthercomponents such as inorganic or organic, solid or liquidpharmaceutically acceptable carriers or vehicles, buffers, excipientsand additives.

Suitable vehicles for topical administration are organic or inorganicsubstances, which are pharmaceutically acceptable and which do not reactwith the active compounds, for example saline, alcohols, vegetable oils,benzyl alcohols, alkylene glycols, polyethylene glycols, glyceroltriacetate, gelatin, carbohydrates such as lactose or starch, magnesium,stearate, talc and petrolatum. The indicated preparations can besterilized and/or contain ancillary substances such as lubricants,preservatives, such as thiomersal (e. g., at 50%), stabilizers and/orwetting agents, emulsifiers, salts to influence the osmotic pressure,buffer substances, colorants, and/or aromatizing substances.

Preferably, a topical excipient is selected that does not enhancedelivery of the agent to the systemic circulation or to the centralnervous system when administered to the ear. For example, in general, itis preferred that the topical excipient has not substantial occlusiveproperties, which enhance percutaneous transmission through the mucosainto the systemic circulation. Such occlusive vehicles includehydrocarbon bases, anhydrous absorption bases such as hydrophilicpetrolatum and anhydrous lanolin (e. g., Aquaphor), and water-in-oilemulsion bases such as lanolin and cold cream. More preferred arevehicles which are substantially non-occlusive, and generally includethose which are water-soluble, such as oil-in-water emulsion bases(creams or hydrophilic ointments) and water-soluble bases such aspolyethylene glycol-based vehicles and aqueous solutions gelled withvarious agents such as methylcellulose, hydroxyethyl cellulose, andhydroxypropylmethylcellulose (e. g., K Y Gel).

Suitable topical excipients and vehicles can be routinely selected for aparticular use by those skilled in the art, and especially withreference to one of many standard texts in the art, such as Remington'sPharmaceutical Sciences, Vol. 18, Mack Publishing Co., Easton, Pa.(1990), in particular Chapter 87. For instance, biologically-activeagents in accordance with the present invention can be combined withenhancing agents which enhance the penetration of an agent.

The pharmaceutical composition containing the active ingredient(s), thebiocompatible polymer(s) and, if necessary, adjuvants, e.g.preservatives, stabilizers, wetting agents, emulsifiers, cross-linkingagents, may be prepared by any of the methods well known in the art ofpharmacy, e.g. by conventional mixing, granulating, confectioning,dissolving or lyophilizing methods.

The composition can be used for the preparation of a medicament fortreating inner ear diseases. Examples are the treatment of tinnitus,hearing loss, inner ear inflammation or infection, autoimmune eardisorder, vertigo, Meniere's Disease, inner ear cell degeneration orage-induced inner ear cell degeneration.

Administration of the inventive composition or medicament to a mammalsuffering from an inner ear disease may be accomplished by variousdelivery techniques. Preferably, it is administered by inserting it intothe middle ear. The medicament resp. implant preferably can beadministered by infusion, injection or by deposition by means of asurgical instrument.

These include the use of devices or drug carriers to transport and/ordeliver the formulation in a targeted fashion to the inner-middle earinterface tissue structures, where it diffuses into the inner ear or isactively infused. Examples are otowicks (see e.g. U.S. Pat. No.6,120,484 to Silverstein), round window catheters (see e.g. U.S. Pat.Nos. 5,421,818; 5,474,529; 5,476,446; 6,045,528; all to Arenberg, orU.S. Pat. No. 6,377,849 and its division 2002/0082554 to Lenarz),microimplants (see e.g. WO2004/064912 by Jukarainen et al.) or deviceswhich are inserted into the cochlear duct or any other part of thecochlea (see e.g. U.S. Pat. No. 6,309,410 to Kuzma). They furtherinclude the use of intratympanic injection, where the formulation isinjected into the middle ear over the area of the target inner-middleear interface tissue structure, such as the round window niche (see e.g.Light J. and Silverstein H., Current Opinion in Otolaryngology & Headand Neck Surgery 12: 378-383 (2004)). The injection may be performeddirectly through the tympanic membrane, through a ventilating tubeinserted into the tympanic membrane, or through an opening of thetympanic membrane (e.g. by tympanomeatal flap). The volume of theformulation to be injected is typically between 200 and 500 microlitres.

Formulations which cannot be injected or infused by any of theaforementioned means may be deposited onto the target inner-middle earinterface structure across a small opening in the tympanic membrane withthe aid of surgical instrument.

The formulation can be administered prior to, during or after the onsetof the inner ear disorder. The amount to be administered may vary,depending upon the method of administration, duration of therapy, thecondition of the subject to be treated, the severity of the inner eardisorder and ultimately will be decided by the attending physician. Theduration of therapy may range between about one hour and several days,weeks or months, and may extend up to chronic treatment. In the case oftherapies of long duration, repeat doses of the formulation may have tobe administered. The therapeutically effective amount of the compound tobe delivered may range between about 0.1 nanogram/hour to about 100micrograms/hour.

A therapeutically effective dose is defined as an amount effective tosuppress or reduce the inner ear disorder in a treated individual. Atherapeutically effective dose is also the amount effective to suppressor reduce the inner ear disorder in the afflicted individual. As statedabove, a therapeutically effective dose may vary, depending on thechoice of specific compound, the specific, condition to be treated andon the method of its administration. For example, a lower dose of aketamine analogue with a higher binding affinity may be more effectivethan ketamine that binds with a lower affinity: As a result,arylcycloalkylamines with higher binding affinities are preferred.

The duration of therapy may also vary, depending on the specific form ofinner ear disorder for which treatment is desired—acute, subacute, orchronic. As a guide, shorter durations of therapy are preferred and aresufficient when the inner ear disorder does not recur once therapy hasceased. Longer durations of therapy may be employed for an individual inwhich the inner ear disorder persists following short therapy.

The present invention is explained in more detail by the followingExamples in conjunction with the attached Figures without limiting thescope of the present invention.

FIG. 1 shows the cumulative release of S-(+)-Ketamine from 5% and 7.5%hyaluronic acid gel formulations into phosphate buffer solution overtime. (A) Ketamine is rapidly released from the gel in the absence of arate limiting membrane; after just one hour almost 50% of the totalcumulative concentration in PBS are already achieved. The concentrationof hyaluronic acid has hardly any effect on the release rate. (B) Theuse of a Franz cell with a dialysis membrane to mimic the round windowmembrane slows down significantly the release of Ketamine into PBS,which now takes about three days. The release rate appears to be muchslower for the higher concentration of hyaluronic acid. (C) When afilter membrane is employed in the Franz cell, the release of Ketamineextends over approximately 60 hours, with the more highly concentratedhyaluronic acid gel releasing more slowly than at the lowerconcentration.

FIG. 2 shows the concentration of S-(+)-Ketamine in perilymph afterbeing released from a 2.8% hyaluronic acid formulation that had beenplaced into the round window niche of guinea pigs and then diffusedacross the round window membrane into the inner ear. Perilymph wassampled to determine Ketamine concentration at the time points 1 hour (1H), 3 hours (3 H), 8 hours (8 H), 24 hours (24 H) and 3 days (3 D).

FIG. 3 shows the concentration of S-(+)-Ketamine in perilymph afterbeing released either from a 0.5% hyaluronic acid formulation or a 20%poloxamer formulation that had been injected onto the round window nicheof guinea pigs and then diffused across the round window membrane intothe inner ear. Perilymph was sampled 3 hours and 48 hours postadministration to determine Ketamine concentrations.

EXAMPLE 1

Methods and Materials

The release of the NMDA receptor antagonist Ketamine, which had beenpreviously shown to be effective in the treatment of cochlear tinnitus,from a hyaluronic acid gel formulation was evaluated in a two stagedapproach. In a first stage, in vitro experiments were performed todetermine the release kinetics of the formulation. These results werethen used as starting point for in vivo studies in animals.

In Vitro Studies

A hyaluronic acid solution (Hylumed, Genzyme Corp.) was prepared atconcentrations of 5 and 7.5% in phosphate buffered saline (PBS). At 8%,handling of the gel had shown to be difficult due to the high viscosity.S-(+)-Ketamine hydrochloride (Sigma-Aldrich) was dissolved at aconcentration of 2% (weight/weight) equivalent to 73 mM. To evaluate theimportance of the drug load factor, concentrations of 0.5% and 2.5% werealso tested. Release of the pharmacologically active agent was measuredin PBS, a common receiver fluid for controlled release studies, eitherwithout any membrane or by using a filter membrane or a dialysismembrane (Spectropore) in a Franz cell (PermeGear). The membranes wereemployed to mimic the rate limiting membrane of the round window. Thetemperature of the fluid was maintained constant at body temperature.The bottom chamber of the Franz cell was filled with 5 ml of PBS as thereceiver fluid. The receiver fluid contained a stir bar for continuousagitation. The upper chamber was filled with approximately 50 mg of geland the cell assembled. At various time points, aliquots (typically 1ml) were withdrawn and analyzed by UV spectrophotometry (Agilent 8453).The absorbance at 215 nm was measured and the concentration calculatedusing an extinction coefficient of 30 ml/mg cm. As the volume of thealiquot was known, the total amount released could be determined. Eachtime an aliquot was withdrawn, the same volume of PBS was placed backinto the Franz cell chamber.

In Vivo Studies

Based on the results of the in vitro studies, various concentrations ofhyaluronic acid (Hylumed Medical, molecular weight 2.4 million, GenzymeCorp.) were tested for their residency in the round window niche andtheir potential effect on hearing through interference with the freemovement of the round window membrane. Hearing thresholds were tested inpigmented guinea pigs by measuring the compound action potential (CAP)of the auditory nerve by an electrode implanted onto the round windowmembrane of the animals (with a reference electrode placed in a neckmuscle). The reference electrode and the round window electrode weresoldered to a plug fixed on the skull. For this purpose andadministration of 2 microlitres of the gel formulation into the roundwindow niche, the bulla of the anaesthetized animal was opened through aposterior auricular surgical procedure (dorsal approach). The bulla wasthen closed again with dental cement (Texton, SS White Manufacturing),the wounds disinfected with a betadine solution and sutured.

First, a gel was prepared at the concentration of 5% in artificialperilymph, which had previously been tested in the in vitro tests, anddeposited with the tip of a previously sterilized surgical instrumentinto the round window niche of a guinea pig. The residency of the gelwithin the niche was visually inspected, i.e. whether the gel flowed outof it or remained in place. The CAP was measured just prior to the geladministration and then again repeatedly after the administration. Asthe viscosity of the gel was too high, and transitory effects on hearingthreshold levels were observed, the gel concentration was then titrateddown (3.5%, 3.2%) to finally 2.8%, a level at which the gel couldconveniently be placed into the round window niche, remained well inplace and no hearing loss was observed. One animal per concentration wastested.

In a second step, a pharmacokinetic study with pigmented guinea pigs wascarried out in order to evaluate in vivo the diffusion of Ketamine froma hyaluronic acid gel formulation across the round window membrane intothe inner ear. A total of 30 animals were tested for concentrations ofthe pharmaceutical compound in the perilymph at 1 hour, 3 hours, 8hours, 24 hours and 72 hours following gel administration; 6 animals pertime point were tested.

Animals were anaesthetized with a single-dose i.p. injection of 0.3ml/kg of pentobarbital at 6% (Ceva sante animale), and the right earbulla was opened using a posterior auricular surgical procedure (dorsalapproach). 2 microlitres of the hyaluronic gel formulation (2.8% HylumedSterile in artificial perilymph, molecular weight 2.44 million; GenzymeCorp.) with S-(+)-Ketamine (Sigma-Aldrich) at a concentration of 1milliM were then deposited onto the round window membrane of the innerear. At each of the aforementioned time points, one group of animals wasdecapitated under deep anaesthesia (pentobarbital 50 mg/kg). The rightcochlea was extracted from the temporal bone and the bulla opened. Asmall hole was then drilled into the cochlea by cochleostomy (diameter0.2 mm) at its base. 10 microliters of perilymph were sampled throughthe hole with a sterile glass micropipette (0.1 mm diameter at the tip),connected by a sterile catheter to a sterile microsyringe. The sampleswere then analyzed by liquid chromatography mass spectrometry with alimit of quantification of 0.2 ng/ml (HPLC instrument: Perkin Elmerseries 200; mass spectrometer detector: MSD Sciex API 4000 AppliedBiosystems; column: Zorbax SB CN 50×2.1 mm 5 μm-Agilent technologies).

Results

In Vitro Studies

As FIG. 1 shows, the hyaluronic acid gel releases Ketamine relativelyquickly, i.e. over just a few hours. The release kinetics aresignificantly altered when a rate limiting membrane is employed, withthe delivery now extending over a few days. At the higher concentrationof 7.5%, the hyaluronic acid gel formulation releases Ketamine lessquickly than at 5%.

The drug load had also a significant influence on release kinetics. Whenthe gel contained 0.5% Ketamine (by weight), the pharmaceutical compoundwas released in a Franz cell with filter membrane nearly as fast as asimple Ketamine hydrochloride solution. Only by increasing the loadingfactor to 2.5% did the release kinetics slow appreciably. The initialburst was quite low, with only about 20% being released in the firsthour. Therefore, it appears that using as high a loading factor aspossible will help extend the release kinetics.

In Vivo Studies

As FIG. 2 shows, the maximum concentration of Ketamine in the perilymphof the inner ear following diffusion across the round window membranefrom a 2.8% hyaluronic acid gel is achieved within one hour.Concentrations then decrease rapidly, with the last quantifiable levelsobserved after three days. Several interesting conclusions can be drawnfrom these results:

-   -   1) The gel formulation has the capacity to release Ketamine into        the inner ear over three days—in spite of a much lower        concentration of hyaluronic acid (2.8% vs. 5 resp. 7.5%) and a        drug load that is about 73 fold lower (0.027% vs. up to 2.5% by        weight) than in the in vitro experiments. It thus seems to be an        attractive type of formulation for the treatment of inner ear        disorders.    -   2) The measured perilymph concentrations of Ketamine appear very        low when compared with the initial concentration of the        pharmacologically active agent in the gel. This may be explained        by loss of the Ketamine into the middle ear, absorption by the        mucosa, the incapacity of the passive diffusion process to pull        more of the pharmaceutical compound into the perilymph, or a        rapid clearance of the drug from the perilymph. In addition, the        sampling technique leads to a downward bias in measured        concentrations, as minimum quantities require that perilymph is        pulled also from parts within the inner ear to which the        pharmaceutical compound has probably not been distributed. I.e.        there is a dilution of concentrations. It is well known in the        Art that concentrations of pharmaceutical compounds within the        cochlea are highest at its base, much lower in the middle turn        and mostly absent in the apical region and beyond (scala        vestibuli).    -   3) Given the many parameters which can influence the release        kinetics from a gel formulation placed into the round window        niche and the diffusion across the round window niche, in vitro        models must be considered as very limited in their ability to        evaluate whether and how a pharmacologically active agent for        the treatment of an inner ear disorder is delivered into the        inner ear. The use of an appropriate in vivo model seems thus to        be imperative.

EXAMPLE 2

While the previous experiments explored release kinetics of Ketaminefrom a rather viscous gel formulation, which could not be injected intothe middle ear, we sought next to evaluate two injectable gelformulations, which offer the advantage of easy handling.

Methods and Materials

A total of 16 pigmented guinea pigs were administered 100 microlitres ofeither a hyaluronic acid (Hylumed Sterile, Genzyme Corp.) or a poloxamer(Lutrol F127, BASF) gel formulation containing S-(+)-Ketaminehydrochloride (Cristalia) through a 1 ml syringe connected to a needle.Half of the animals received 0.5% hyaluronic acid gel prepared in aphosphate buffered solution at pH 7.4 prepared in accordance with theEuropean Pharmacopeia (ref. 4005000). The Ketamine was dissolved in thegel at a concentration of 1 mM with a magnetic stirrer over night at 4degrees Celcius. The remaining half of the animals received a 20%poloxamer gel also through a 1 ml syringe connected to a needle. The gelwas prepared by adding slowly 600 mg of Lutrol powder to 3 ml of thesame phosphate buffered solution in a magnetic stirrer (500 rpm). Themixing process continued then for 16 hours to obtain a clear solutionwith minimum viscosity. As for the hyaluronic acid gel, the Ketamine wasdissolved in the poloxamer solution at a concentration of 1 mM with amagnetic stirrer over night. Immediately after contact with the middleear tissue of the guinea pigs, the poloxamer gelified and became almostsolid.

In order to inject the gel formulations, the guinea pigs wereanaesthetized with a single-dose i.p. injection of 0.3 ml/kg ofpentobarbital at 6% (Ceva santé animate) and the right butta of theanimal was opened through a posterior auricular surgical procedure(dorsal approach). The bulla was then closed again with dental cement(Texton, SS White Manufacturing), the wounds disinfected with a betadinesolution and sutured. After 3 hours, 4 animals of each gel formulationgroup were decapitated under deep anaesthesia (pentobarbital 50 mg/kg)to sample the perilymph, with the remaining animals being sacrificedafter 48 hours. The right cochlea was extracted from the temporal boneand the bulla opened. A small hole was then drilled into the cochlea bycochleostomy (diameter 0.2 mm) at its base. 10 microliters of perilymphwere sampled through the hole with a sterile glass micropipette (0.1 mmdiameter at the tip), connected by a sterile catheter to a sterilemicrosyringe. The samples were then analyzed by liquid chromatographymass spectrometry with a limit of quantification of 0.2 ng/ml (HPLCinstrument: Perkin Elmer series 200; mass spectrometer detector: MSDSciex API 4000 Applied Biosystems; column: Zorbax SB CN 50×2.1 mm 5μm-Agilent technologies).

Results

As FIG. 3 shows, the use of a less viscous hyaluronic acid formulationdid not change significantly the concentration in the perilymph at thetime points of 3 hours and 48 hours after administration. This showsthat an injectable formulation provides for a similar concentration inthe inner ear. FIG. 3 further shows that poloxamers also provide foreffective release across the round window membrane, whereas theconcentration in perilymph at three hours was more than double than thatof the hyaluronic acid concentration. This may be due to differentrelease kinetics or to the fact that the solidification of the gelwithin the round window niche, which fixed it locally, allowed for abetter contact with the round window membrane. After 3 hours, parts ofthe much more fluid hyaluronic acid formulation may already have drainedfrom the round window niche respectively even the middle ear space downinto the pharynx.

1-25. (canceled)
 26. A method of treating an inner ear diseasecomprising administering to a patient in need thereof a controlledrelease composition comprising a pharmaceutically active agent and athermosetting polymer; wherein the pharmaceutically active agent isselected from steroids, and the thermosetting polymer has a gelationtemperature of at least about 15° C.
 27. The method of claim 26, whereinthe pharmaceutically active agent is suspended in the composition. 28.The method of claim 27, wherein the composition is a suspension in whichthe pharmaceutically active agent is dispersed within the thermosettingpolymer.
 29. The method of claim 26, wherein the thermosetting polymeris poloxamer.
 30. The method of claim 29, wherein the poloxamer isLutrol F127 (poloxamer 407).
 31. The method of claim 30, wherein thepoloxamer has a concentration of about 20% (w/w).
 32. The method ofclaim 26, wherein the composition provides controlled release of thepharmaceutically active agent over an extended period of time of one ormore days.
 33. The method of claim 26, wherein the pharmaceuticallyactive agent is dexamethasone.
 34. The method of claim 26, wherein thecomposition further comprises a phosphate which buffers the pH of thecomposition to about 7.4.
 35. The method of claim 26, wherein thecomposition is contained in a syringe optionally connected to a needle.36. The method of claim 35, wherein a single dose of the composition inthe syringe is about 200 μL to about 500 μL.
 37. The method of claim 26,wherein the composition is administered by inserting it into the middleear.
 38. The method of claim 26, wherein the composition is administeredby infusion, injection, or by deposition by means of a surgicalinstrument.
 39. The method of claim 26, wherein the inner ear disease isselected from the group consisting of tinnitus, hearing loss, inner earinflammations or infections, auto-immune disorders, vertigo, andMeniere's Disease.
 40. The method of claim 39, wherein the tinnituscomprises cochlear tinnitus.
 41. The method of claim 26, wherein theinner ear disease is excitotoxicity-induced ear cell degeneration orage-induced ear cell degeneration.
 42. The method of claim 26, whereinthe treatment comprises reducing the perception of tinnitus or sound.43. The method of claim 41, wherein the inner ear disease is Meniere'sDisease.